Carboxylate-Assisted Ruthenium(II)-Catalyzed C-H Alkylation and Alkenylation

(1)

Alkylation and Alkenylation

Dissertation

zur Erlangung des mathematisch-naturwissenschaftlichen Doktorgrades

"Doctor rerum naturalium"

der Georg-August-Universität Göttingen

im Promotionsprogramm Chemie

der Georg-August University School of Science (GAUSS)

vorgelegt von

Carina Tirler

aus Engelskirchen

Göttingen, 2015

(2)

Prof. Dr. L. Ackermann, Institut für Organische und Biomolekulare Chemie

Prof. Dr. D. Stalke, Institut für Anorganische Chemie

Mitglieder der Prüfungkommission

Referent: Prof. Dr. L. Ackermann, Institut für Organische und Biomolekulare Chemie

Korreferent: Prof. Dr. D. Stalke, Institut für Anorganische Chemie

Weitere Mitglieder der Prüfungskommission:

Dr. A. Breder, Institut für Organische und Biomolekulare Chemie

Prof. Dr. B. Geil, Arbeitsgruppe Prof. Dr. Andreas Janshoff, Institut für Physikalische Chemie

Prof. Dr. C. Höbartner, Institut für Organische und Biomolekulare Chemie

Prof. Dr. S. Schneider, Institut für Anorganische Chemie

Tag der mündlichen Prüfung: 29. 9. 2015

(3)

Mein besonderer Dank gilt meinem Doktorvater Herr Prof. Dr. Lutz Ackermann für die gute Betreuung während der Anfertigung meiner Dissertation und für die mir gegebene Möglichkeit, auf interessanten Themengebieten zu forschen.

Herrn Prof. Dr. Dietmar Stalke danke ich für die freundliche Übernahme des Zweitgutachtens und die gute Unterstützung als Zweitbetreuer.

Frau Prof. Dr. C. Höbartner und den Herren Dr. A. Breder, Prof. Dr. B. Geil und Prof. Dr. S.

Schneider danke ich für die Teilnahme an der Prüfungskommission.

Der gesamten Belegschaft der analytischen Abteilungen unter Herr Machinek und Dr.

Frauendorf danke ich für die schnellen und gewissenhaften Messungen und besonders Herr Machinek persönlich möchte ich für die interessanten und lehrreichen Diskussionen danken.

Meinen Kollegen Fanzhi Yang, Sebastian Lackner und Phani Kumar danke ich besonders für das aufmerksame und zügige Korrekturlesen dieser Arbeit.

Spezieller Dank gebührt auch Stefan Beußhausen, „Gabi“ Keil-Knepel und Karsten Rauch für ihre unentbehrliche Unterstützung im Zusammenhang mit EDV, Verwaltung und Laborequipment.

Ich bin natürlich auch allen Arbeitskreismitgliedern, die mich in technischer, fachlicher oder freundschaftlicher Weise unterstützt haben, dankbar. Den vielen Mitarbeitern und Mitstreitern, die mit mir das Labor geteilt haben, danke ich für das entspannte Arbeitsklima.

Mein besonderer Dank gilt hierbei Dr. Christoph Kornhaaß und den ehemaligen Laborkollegen aus den Laboren 203 und P123.

Ganz besonders möchte ich mich bei meinen Freunden Jennifer Więcek und Laura Eiden bedanken, die immer für mich da waren.

Mein größter Dank geht an meine Familie. Meine Eltern und meine Schwester Claudia, die mich immer unterstütz haben.

(4)

(5)

Abbreviations

Ac Acetyl

Ad Adamantyl

Alk Alkyl

AMLA Ambiphilic metal-ligand activation

aq. aqueous

Ar Aryl

atm Atmosphere

9-BBN 9-Borabicyclo[3.3.1]nonan

Bn Benzyl

Boc tert-Butyloxycarbonyl

bpy 2,2’-Bipyridine

Bu Butyl

cat. Catalytic

CMD Concerted metalation-deprotonation Cp* 1,2,3,4,5-Pentamethylcyclopentadienyl

Cy Cyclohexyl

dba Dibenzylidenaceton

DCE 1,2-Dichloroethane

DG Directing group

diglyme Diglycol methyl ether

DMA N,N-Dimethylacetamide

DMAP 4-(Dimethylamino)-pyridin

DME 1,2-Dimethoxyethane

DMEDA N,N′-Dimethylethylenediamine

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

DoM Directed ortho-metalation

El Electron ionization

ESI Electronspray ionization

Et Ethyl

EWG Electron withdrawing group

FTICR Fourier transform ion cyclotron resonance GC-MS Gas transform ion cyclotron resonance

gem Geminal

h Hour

Hex Hexyl

(9)

HMDS Hexamethyldisilazan

HR-MS High resolution mass spectrometry IES Internal electrophilic substitution i-Pr iso-Propyl

IR Infrared

LDA Lithiumdiisopropylamid

M Metal

Mes 2,4,6-Trimethylphenyl

Me Methyl

m meta

mol. Molecular

M.p. Melting point

M.r. Melting range

NMP N-Methyl-2-pyrrolidone

o ortho

p para

cymene 4-iso-Propyltoluene PEG Polyethylene glycol

Pent. Pentyl

Phen. Phenanthroline

Ph Phenyl

Piv Pivalyl

PMP para-Methoxyphenyl

ppm Parts per million

SEAr Electrophilic aromatc substitution SPO Secondary phosphine oxid

T Temperature

t-Am tert-Amyl

Tf Triflouromethanesulfonyl

TFA Triflouroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TM Transition metal

TMS Trimethylsilyl

TS Transition state

UV Ultraviolet

X Halide

(10)

(11)

1 Introduction

Sustainability is important, because our natural sources are limited and our environment needs protection. Organic chemistry has to face this challenge.

Thus, one of the major goals of sustainable chemistry is the site- and chemo-selective synthesis of organic compounds, without side-products and waste, in a step-economical fashion under mild reaction conditions.

During the last decades, progress has been made in the important field of C−C bond formations.¹ The transition metal-catalyzed cross-coupling reactions,² forming chemo- and site-selective C−C bonds, were developed by several research groups.³ Because of their pioneering work Heck, Negishi and Suzuki were awarded with the Nobel prize in chemistry in 2010, thus illustrating the importance of this methodology.⁴

The traditional cross coupling reaction is presented in Scheme 1.1.

Scheme 1.1: Traditional cross-coupling reaction.

In general, an aryl, alkenyl or alkyl (pseudo)halide reacts as an electrophile with an organometallic reagent as a nucleophile via transition metal catalysis. The key features of the mechanism of cross-coupling reactions are the oxidative addition of the (pseudo)halide to the active catalyst, the transmetalation with the organometallic reagent and the subsequent reductive elimination to give the coupled product. In the Mizoroki-Heck reaction the product is formed via syn-insertion, followed by σ-bond rotation and β-hydride elimination.⁵ Because of the use of prefunctionalized starting materials and the stoichiometric amounts of metal salts produced as side products this transformation is not ideal. To avoid the disadvantages of the

1 (a) A. Behr, Angewandte homogene Katalyse, Wiley-VCH, Weinheim, 2008; (b) Modern Arylation Methods, (Ed.:

L. Ackermann), Wiley-VCH, Weinheim, 2009; (c) G. Fu, Acc. Chem. Res. 2008, 41, 1555–1564; (d) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461–1473.

2 (a) C. C. C. Johansson Seechurn, M. O. Kitching, T.J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51, 5062–5086. (b) Metal-Catalyzed Cross-Coupling Reactions (Eds. de Meijere, A.; Diederich, F.), 2nd ed., Wiley- VCH: Weinheim, 2004. (c) Transition Metals for Organic Synthesis (Eds. Beller, M.; Bolm, C.), 2nd ed., Wiley- VCH: Weinheim, 2004.

3 For recent reviews on conventional cross-coupling reactions, see: (a) Chem. Soc. Rev. 2011, 40, Special Issue 10 "Cross coupling reactions in organic synthesis", 4877–5208; (b) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346–1416; (c) G. Cahiez, A.

Moyeux, A. Chem. Rev. 2010, 110, 1435–1462.

4 "The Nobel Prize in Chemistry 2010 - Press Release". Nobelprize.org. Nobel Media AB 2013. Web. 25 Feb.

2014. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/press.html

5 J. P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–2710.

(12)

cross-coupling reactions several research groups studied the transition metal-catalyzed direct functionalization of C−H bonds.⁶

1.1 Transition Metal Catalyzed C−H Bond Functionalization

Unlike traditional cross-coupling reactions, direct C−H bond functionalizations⁶ have the advantage that prefunctionalized starting materials are not needed. Scheme 1.2 shows three different strategies for transition metal-catalyzed direct C−H bond functionalizations.⁷

Scheme 1.2: Strategies for transition metal-catalyzed C−H bond functionalization

In reference to traditional cross-coupling reactions, Scheme 1.2 a presents the coupling of aryl or alkenyl substrates with an unactivated C−H bond and aryl or alkenyl (pseudo)halides.

In contrast, the reaction in Scheme 1.2 b displays the coupling between arenes or alkenes with organometallic reagents. The last strategy demonstrates the dehydrogenative coupling by activation of two C−H bonds (Scheme 1.2 c). For the latter two transformations,

6 For recent reviews on C–H bond functionalizations, see (a) S. De Sarkar, W. Liu, S. I. Kozhushkov, L.

Ackermann, Adv. Synth. Catal. 2014, 356, 1461–1479; (b) K. Gao, N. Yoshikai, Acc. Chem. Res. 2014, 47, 1208−1219; (c) B. Li, P. H. Dixneuf, Chem. Soc. Rev. 2013, 42, 5744–5767; (d) T. A. Ramirez, B. G. Zhao, Y.

Shi, Chem. Soc. Rev. 2012, 41, 931–942; (e) Z.-Z. Shi, C. Zhang, C.-H. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3381–3430; (f) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2012, 45, 814–825;

(g) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170–1214; (h) L. Ackermann, Chem. Comm. 2010, 46, 4866- 4877; (i) T.W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169; (j) A. A. Kulkarni, O. Daugulis, Synthesis, 2009, 4087–4109; (k) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38, 3242–3272; (l) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu. Angew. Chem. Int. Ed. 2009, 48, 5094–5115. For reports on atom- and step-economy, see: (m) B. M. Trost, Acc. Chem. Res. 2002, 35, 695–705; (n) B. M. Trost, Science, 1991, 254, 1471–1477; (o) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.

2008, 41, 40–49.

7 L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–9826.

(13)

stoichiometric amounts of oxidants are essential. While the two first strategies still need at least some prefunctional starting materials, the dehydrogenative coupling is the most step- and atom-economical reaction, as it does not require any prefunctionalized starting materials.

This is in accordance with the concept of green chemistry.⁸

The transition metal-catalyzed C−H bond functionalization emerged also from the concept of green chemistry. The C−H bond functionalizations could be carried out chemo-, site-, and enantioselectively with a variety of transition metals such as palladium,^6g,6k,6l ruthenium,^6a,6c rhodium,^6f cobalt^6b,6j and nickel.^6j The varieties of these reactions lead to intensive investigations of the catalyst´s working mode. As a consequence, four generally accepted mechanistic pathways⁹ for the C−H bond metalation step were postulated (Scheme 1.3).

Computational studies of these mechanisms were summarized by Eisenstein and co- workers.¹⁰

Scheme 1.3: Possible mechanisms for C−H bond metalation by transition metal complexes.^8c

The first pathway considered, is the oxidative addition (Scheme 1.3 a), which can be performed by electron rich and low-valent complexes of late transition metals. Whereas early transition metals with d⁰-configuration cannot undergo oxidative addition, σ-bond metathesis (Scheme 1.3 b) takes usually place here. While electrophilic substitution (Scheme 1.3 c) occurs with electron deficient late transition metals, alkylidene or imido complexes of early transition metals display the possibility of C−H activation via 1,2-additions (Scheme 1.3 d).

8 Ackermann, L.; Kapdi, A. R.; Potukuchi, H. K.; Kozhushkov, S. I. In Handbook of Green Chemistry (Ed. Li, C.-J.), Wiley-VCH: Weinheim, 2012, 259–305.

9 (a) Y. Boutadla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Bahamonde, Dalton Trans. 2009, 5820–5831; (b) L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.

10 D. Balcells, E. Clot, O. Eisenstein, Chem. Rev. 2010, 110, 749–823.

(14)

New developments display a bifunctional process, which involves C−H activation by an electrophilic metal working synergistically with secondary phosphine oxides or carboxylates.

Six membered transition states are formed during this mechanism, which was coined as CMD¹¹ (concerted-metalation-deprotonation) or AMLA^9a (ambiphilic metal-ligand activation) (Scheme 1.4).

Scheme 1.4: Proposed transition states for the CMD/AMLA activation.

These mechanistical investigations are the foundation of the transition metal-catalyzed C−H bond functionalization, which has gained a lot of attention in recent years and is used for the catalyzed synthesis of biaryls.^{1b, 12}Transition metals used in C−H bond functionalization are relatively expensive. The prices of gold, platinum, rhodium, palladium, iridium and ruthenium are 1174, 1084, 900, 671, 550 and 45 US$ per troy oz, respectively.¹³

Ruthenium, a relatively inexpensive transition metal, proved to be broadly applicable in the C−H bond functionalization. Early studies on chelation-assisted ruthenium(II)-catalyzed direct arylations were performed by the Ackermann group in 2005. The ruthenium-catalyzed arylation of aryl pyridines or aromatic imines with easily accessible aryl chlorides proceeded with excellent chemo- and site-selectivity. This reaction featured a notable functional group tolerance and an excellent catalytic activity (Scheme 1.5).¹⁴

11 D. Lapointe, K. Fagnou, Chem. Lett. 2010, 39, 1118–1126.

12 Selected reviews: (a) L. Ackermann, A. R. Kapdi, H. K. Potukuchi, S. I. Kozhushkov, In Handbook of Green Chemistry (Ed. Li, C.-J.), Wiley-VCH: Weinheim, 2012, 259–305; (b) A. A. Kulkarni, O. Daugulis, Synthesis, 2009, 4087–4109; (c) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42, 1074–1086; (d) D.

Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238; (e) F. Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082–1146; (f) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173–1193; (g) T. Brückl, R. D.

Baxter, Y. Ishihara, P. S. Baran, Acc. Chem. Res. 2012, 45, 826–839; (h) S. H. Cho, J. Y. Kim, J. Kwak, S.

Chang, Chem. Soc. Rev. 2011, 40, 5068–5083.

13 Price metals https://www.quandl.com/collections/markets/palladium 1. 7. 2015.

14 L. Ackermann, Org. Lett. 2005, 7, 3123−3125.

(15)

Scheme 1.5: Ruthenium-catalyzed arylations with aryl chlorides.¹⁴

Inspired by this inexpensive catalytic system the group of Prof. Ackermann focused on ruthenium(II)-catalyzed C−H bond functionalization. An extensive screening of different additives for ruthenium(II)-catalyzed arylations of aryl triazoles identified hindered carboxylic acids to be excellent ligands.¹⁵ As can be seen in the previous example of ruthenium(II)- catalyzed arylation reaction, the site-selectivity is of great importance in C−H bond activation and remains a challenging issue.

1.2 Site-Selectivity

In particular site-selectivity was either obtained by enhanced acidity of a specific (hetero)aromatic C−H bond or by a Lewis basic directing group for the conversion of substrates into ortho-functionalized derivatives (Scheme 1.6).¹⁶

15 (a) L. Ackermann, M. Mulzer, Org. Lett. 2008, 10, 5043–5045; (b) L. Ackermann, R. Born, R. Vicente, ChemSusChem, 2009, 546–549; (c) L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008, 10, 2299–2302.

16 (a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624–655; (b) For a review on removable directing groups (DG) see: C. Wang, Y. Huang, Synlett, 2013, 24, 145–149.

(16)

Scheme 1.6: Two strategies for site-selective C−H bond functionalization

In both cases stoichiometric amounts of bases are necessary. The latter is the most common approach in direct C−H bond activation. The directing group contains a heteroatom with a lone pair of electrons that coordinates to the transition metal. During the last years, several heteroatom bearing directing groups (Scheme 1.7) have been introduced in palladium-, nickel-, rhodium-, ruthenium-, or iridium-catalyzed C−C bond formation.^7,^{6h, 17}

Scheme 1.7: Directing groups in transition metal catalyzed C−C bond formation.

The directed ortho-metalation (DoM) mandates a similar approach, however using stoichiometric amounts of main group metals.¹⁸ This concept was initially developed by Gilman¹⁹ and Wittig²⁰ utilizing organolithium compounds (Scheme 1.8) and was extensively investigated by Snieckus.²¹

17 (a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238; (b) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946; (c) S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4, 886–896.

18 J. P. Fleming, M. B. Berry, J. M. Brown, Org. Biomol. Chem. 2008, 6, 1215–1221.

19 Gilman, H.; Bebb, R.L. J. Am. Chem. Soc. 1939, 61, 109–112.

20 B. G. Hashiguchi, S. M. Bischof, M. M. Konnick, R. A. Periana, Acc. Chem. Res. 2012, 45, 885–898.

21 Snieckus, V. Chem. Rev. 1990, 90, 879–933.

(17)

Scheme 1.8: DoM of a pyridine derivative.²²

A great disadvantage of this strategy is the formation of stoichiometric amounts of lithium salts, as by-products. Moreover, the limited functional group tolerance is a major drawback, which is due to the high reactivity of the strong bases.

However, ortho-functionalization could be achieved quite easily, while meta- and para- functionalization remained challenging. Recently, Knochel made some progress in meta- and para-selective functionalization, using stoichiometric amounts of organomagnesium compounds in combination with several directing groups.²³ Furthermore, Brown and co- workers developed a meta-selective substitution with organolithiums and sulfoxides as removable directing group.¹⁸

Nevertheless, because of the disadvantages of the stoichiometric DoM-type reactions, such as the stoichiometric use of strong bases and the removal of the directing group, they cannot be considered as step- or atom-economical.

In 2012, Yu and co-workers developed a meta-selective palladium-catalyzed direct alkenylation applying an end-on template (Scheme 1.9) with easily removable directing group.²⁴

Scheme 1.9: Direct meta-alkenylation by Yu.²⁴

Meta-selective reactions catalyzed by transition metals remained scarce. In 2009, the Gaunt group published a copper-catalyzed meta-arylation of anilides.²⁵ Shortly after this, the

22 S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946.

23 (a) C. J. Rohbogner, G. C. Clososki, P. Knochel, Angew. Chem. Int. Ed. 2008, 47, 1503–1507; (b) G. Monzón, I. Tirotta, P. Knochel, Angew. Chem. Int. Ed. 2012, 51, 10624–10627.

24 (a) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature, 2012, 486, 518–522; (b) J. Li, S. De Sarkar, L. Ackermann, Top.

Organomet. Chem. 2015, DOI:10.1007/3418_2015_130.

(18)

research group published the para-selective arylation of phenols and anilines.²⁶ Both reactions were subsequently being shown to be Brønsted-acid-catalyzed transformations.

Ruthenium-catalyzed meta-selective C−H bond functionalizations are rare. Frost and co- workers reported the ruthenium-catalyzed meta-selective sulfonylation of 2-phenylpyridines (Scheme 1.10).²⁷ A drawback of the directing group is that it cannot be cleaved.

Scheme 1.10: Meta-selective sulfonylation of 2-phenylpyridine reported by Frost.

Outstandingly, Ackermann and co-workers published the first ruthenium-catalyzed meta- selective alkylation of arenes (Scheme 1.11).²⁸

Scheme 1.11: Meta-selective C−H alkylation by Ackermann.

In spite of this example of meta-selectivity in alkylation reactions there is still a challenge, which has to be faced in the site-selective transition metal-catalyzed alkylation. In the past decade several research groups extensively investigated the site-selective alkylation reaction via C−H bond functionalization.²⁹

25 (a) R. J. Phipps, M. J. Gaunt, Science, 2009, 323, 1593–1597. For mechanistic DFT calculations, see: (b) S.-I.

Zhang, Y. Ding, Chin. J. Chem. Phys. 2011, 24, 711–723; (c) B. Chen, X.-L. Hou, Y.-X. Li, Y.-D. Wu, J. Am.

Chem. Soc. 2011, 133, 7668–7671.

26 C.-L. Ciana, R. J. Phipps, J. R. Brandt, F.-M. Meyer, M. Gaunt, J. Angew. Chem. Int. Ed. 2011, 50, 458–462.

27 O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn, M. K. Whittlesey, C. G. Frost, J.

Am. Chem. Soc. 2011, 133, 19298–19301.

28 N. Hofmann, L. Ackermann, J. Am. Chem. Soc. 2013, 135, 5877−5884.

29 L. Ackermann, Chem. Commun. 2010, 46, 4866−4877.

(19)

1.3 Alkylation Reactions of Arenes

1.3.1 Friedel-Crafts Alkylation

The beginning of alkylation reaction was constituted by the Friedel-Crafts alkylation.³⁰ Untill today the reaction plays an important role and is employed on industrial scale. The synthesis of ethylbenzene from benzene and ethylene is arguably the largest C−C bond formation process used in industry (Scheme 1.12).³

Scheme 1.12: Friedel-Crafts reaction of benzene 4a.

Still this alkylation reactions face some disadvantages, which include the use of corrosive reagents, harsh reaction conditions and undesired side products. Besides these problems the reaction was continously impoved.³¹

An elegant solution to avoid the disadvatages of the Friedel-Crafts alkylation reaction is represented by the homogenous transition metal catalysis.

1.3.2 Cross-Coupling Reactions

Transition metal-catalyzed cross-coupling alkylating reactions are rare and have some difficulties when using unactivated alkyl (pseudo)halides. Two difficulties have to be faced in these reactions specifically for the alkyl halides. First, they process low reactivity, because of their electron-rich character. Second, they easily undergo β-hydride eliminations.

Nevertheless, among this Fu demonstrated sucessfully the nickel-catalyzed Suzuki-Miyaura cross-coupling with tertiary alkyl halides (Scheme 1.13).³²

30 (a) C. Friedel, J. M. Crafts, Compt. Rend. 1877, 84, 1392–1450; (b) C. Friedel, J. M. Crafts, J. Chem. Soc.

1877, 32, 725–791.

31 (a) M. Rüping, B. J. Nachtsheim, Beilstein J. Org. Chem. 2010, 6, 1–24; (b) T. Tsuchimoto, K. Tobita, T.

Hiyama, S.-I. Fukuzawa, Synlett, 1996, 557–559; (c) Catalytic Asymmetric Friedel-Crafts Alkylations (Eds.:

Bandini, M.; Umani-Ronchi, A.), Wyley-VCH: Weinheim, 2009.

32 S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 624–627.

(20)

Scheme 1.13: Nickel-catalyzed cross-coupling of tert. alkyl halides.

Moreover, Fu put a lot of effort in the development of alkyl cross coupling reactions, which succeeded in the alkyl-alkyl Negishi³³ and Suzuki-Miyaura³⁴ couplings in recent years.

Despite these improvements the advantages of transition metal-catalyzed C−H bond functionalization dominate.

1.3.3 Transition Metal-Catalyzed C−H Bond Alkylation

The transition metal-catalyzed C−H bond alkylation can be achieved by two different ways, namely the hydroarylation of alkenes (Scheme 1.14 a) and the alkylation with unactivated alkyl halides (Scheme 1.14 b).

Scheme 1.14: Transition metal-catalyzed alkylation.

Pioneering work on the regioselective ortho-alkylation by hydroarylation of alkenes was done by Lewis and Smith in 1986 (Scheme 1.15).³⁵

33 (a) J. T. Binder, C. J. Cordier, G. C. Fu, J. Am. Chem. Soc. 2012, 134, 17003–17006. (b) J. Choi, G. C. Fu, J.

Am. Chem. Soc. 2012, 134, 9102–9105. (c) Oelke, A. J.; Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 2966–2969. (d) S. W. Smith, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 12645–12647.

34 (a) A. Wilsily, F. Tramutola, N. A. Owston, G. C. Fu, J. Am. Chem. Soc. 2012, 134, 5794–5797. (b) S. L.

Zultanski. G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362–15364. (c) B. Saito, G. C. Fu, J. Am. Chem. Soc.

2008, 130, 6694–6695. (d) S. Lu, G. C. Fu, Angew Chem. In. Ed. 2010, 49, 6676–6678. (e) B. Saito, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 9602–9603.

35 A review: (a) L. N. Lewis, J. F. Smith, J. Am. Chem. Soc. 1986, 108, 2728–2735; (b) P. B. Arockiam, C.

Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879–5918.

(21)

Scheme 1.15: Ruthenium(0)-catalyzed alkylation of phenol with ethylene.

The hyroarylation using ruthenium hydride complexes as catalysts was extended by Murai, Chatani and Kakiuchi in 1993³⁶ and is today known as the Murai reaction (Scheme 1.16).

The main disadvantage of this reaction, the air sensitivity of the catalyst, could be solved by Darses and Genet using the in situ formed catalyst [RuH2(PPh)3)4].³⁷

Scheme 1.16: Ruthenium(0)-catalyzed Murai-reaction.

An early example of the transition metal-catalyzed alkylation with alkyl (pseudo)halides was the palladium-catalyzed entropically-favored intramolecular direct alkylation for the synthesis of oxindoles 38 by Hennessy and Buchwald (Scheme 1.17).³⁸

Scheme 1.17: Palladium-catalyzed intramolecular direct alkylation for the synthesis of oxindoles 40.

36 (a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani, Nature, 1993, 366, 529–

531. (b) F. Kakiuchi, S. Murai, Acc. Chem. Res. 2002, 35, 826–834. For DFT-calculations, see: (c) U.

Helmstedt, E. Clot, Chem. Eur. J. 2012, 18, 11449–11458. For ruthenium-catalyzed Murai-type carbonylations, see: (d) N. Chatani, Y. Ie, F. Kakiuchi, S. Murai, Org. Chem. 1997, 62, 2604–2610.

37 (a) R. Martinez, R. Chevalier, S. Darses, J.-P. Genet, Angew. Chem. Int. Ed. 2006, 45, 8232–8235; (b) R.

Martinez, M.-O. Simon, R. Chevalier, C. Pautigny, J.-P. Genet, S. Darses, J. Am. Chem. Soc. 2009, 131, 7887–

7895.

38 E. Hennessy, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 12084–12085.

(22)

A number of nickel- and palladium-catalyzed alkylation reactions limited to heteroarenes were reported by Hu,³⁹ Ackermann⁴⁰ and Miura and Satoh.⁴¹

In spite of this challenging task, the transition metal-catalyzed direct ortho-alkylation with inexpensive ruthenium catalysts was achieved by Ackermann and co-workers. In 2009, Ackermann reported the ruthenium(II)-catalyzed C−H alkylation of arylpyridines with unactivated alkyl halides (Scheme 1.18). The scope was not limited to pyridines as directing group, but could be extended to pyrazoles and ketimines (Scheme 1.18).⁴²

Scheme 1.18: Ruthenium(II)-catalyzed direct ortho-alkylation by Ackermann.

The benefits of the ruthenium(II)-catalyzed direct alkylations are that no β-hydride elimination of the alkyl halides takes place. Furthermore, inexpensive non prefunctionalized starting materials could be used. Fortunately, the inexpensive carboxylate-assisted catalytic system developed in the ruthenium(II)-catalyzed arylation reactions^15c proved to be broadly applicable in the ruthenium-catalyzed alkylation. These outstanding site-selective C−C bond formations represent a further element in the transition metal-catalyzed C−H bond functionalization and therefore improved sustainability of organic chemistry.

39 (a) P. Ren, I. Salihu, R. Scopelliti, X. Hu, Org. Lett. 2012, 14, 1748−1751; (b) O. Vechorkin, V. Proust, X. Hu, Angew. Chem. Int. Ed. 2010, 49, 3061−3064.

40 L. Ackermann, B. Punji, W. Song, Adv. Synth. Catal. 2011, 353, 3325−3329.

41 T. Yao, K. Hirano, T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 12307−12311.

42 L. Ackermann, P. Novák, R. Vicente, N. Hofmann, Angew. Chem. Int. Ed. 2009, 48, 6045–6048.

(23)

1.4 Transition Metal-Catalyzed C−H Bond Alkenylation

The first synthesis of economically relevant styrene derivatives, which are key structural motifs in natural products, via transition metal-catalyzed oxidative alkenylation was published in 1967 by Fujiwara and Moritani.⁴³ The reaction was first conducted with a palladium- styrene-complex, which reacted with the arene, yielding the stilbene (Scheme 1.19 a).

Immediately after this the amount of the palladium complex could be reduced to catalytic amounts (Scheme 1.19 b).

Scheme 1.19: Fujiwara-Moritani-Reaction.

Thereupon, various applications of palladium catalysts with different oxidants and additives on different substrates were systematically studied.⁴⁴

The search of efficient transition metal-catalysts for C−C bond formation led to rhodium catalysis. In recent years various efficient and selective, yet relatively expensive rhodium catalysts were used for the oxidative alkenylation (Scheme 1.20).⁴⁵

43 (a) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967, 12, 1119–1122; (b) Y. Fujiwara, I. Moritani, M.

Matsuda,Tetrahedron 1968, 24, 4819-4824.

44 (a) S. R. Kandukuri, J. A. Schiffner, M. Oestreich, Angew. Chem. Int. Ed. 2012, 51, 1265–1269; (b) Y.-H. Xu, J.

K. Cheng, M. T. Low, T.-P. Loh, Angew. Chem. Int. Ed. 2012, 51, 5701–5705; (c) C. Wang, H. Ge, Chem.–Eur.

J. 2011, 17, 14371–14374; (d) H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang, J.-Q. Yu, J. Am. Chem.

Soc. 2011, 133, 7222–7228; (e) D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 327, 315–319;

(f) M. Miyasaka, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2010, 75, 5421–5424; (g) B.-F. Shi, Y.-H. Zhang, J. K. Lam, D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 460–461; (h) Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072–5074; (i) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1159–1162; (j) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. Int. Ed. 2005, 44, 3125–3129; (k) M. Dams, D. E. De Vos, S. Celen and P. A. Jacobs, Angew. Chem. Int. Ed. 2003, 42, 3512–

3515; (l) M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries P. W. N. M.

van Leeuwen, J. Am. Chem. Soc. 2002, 124, 1586–1587; (m) M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art, M.

Nomura, J. Org. Chem. 1998, 63, 5211–5215.

(24)

Scheme 1.20: Selected examples of rhodium-catalyzed alkenylations.

The use of cheaper ruthenium-catalysts was reported by Milstein in 2001 (Scheme 1.21).⁴⁶

Scheme 1.21: Oxidative alkenylation of arenes by Milstein.

The scope of this reaction was limited to simple arenes and methyl acrylate as alkene.

Notably, the reaction worked without directing group and with oxygen as the terminal oxidant, albeit under high pressure and harsh reaction conditions. The ruthenium-catalyzed reaction

45 (a) J. Mo, S. Lim, S. Park, T. Ryu, S. Kim, P. H. Lee, RSC Adv. 2013, 3, 18296–18299; (b) Y. Yokoyama, Y.

Unoh, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2014, 79, 7649−7655; (c) T. Iitsuka, P. Schaal, K Hirano, T.

Satoh, C. Bolm, M. Miura, J. Org. Chem. 2013, 78, 7216−7222; (d) S. Kathiravan, I. A. Nicholls, Eur. J. Org.

Chem. 2014, 7211–7219; (e) B. Li, J. Ma, W. Xie, H. Song, S. Xu, B. Wang, Chem. Eur. J. 2013, 19, 11863–

11868; (f) Z. Song, R. Samanta, A. P. Antonchick, Org. Lett. 2013, 15, 5662−5665. (g) N.-J. Wang, S.-T. Mei, L.

Shuai, Y. Yuan, Y. Wie, Org. Lett. 2014, 16, 3040−3043; (h) P. Zhao, R. Niu, F. Wang, K. Han, X. Li, Org. Lett.

2012, 14, 4166−4169; (i) Y. Unoh, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2015, 17, 704−707; (j) Y. Wang, C.

Li, Y. Li, F. Yin, X.-S. Wanga, Adv. Synth. Catal. 2013, 355, 1724–1728.

46 H. Weissman, X. Song, D. Milstein, J. Am. Chem. Soc. 2001, 123, 337–338.

(25)

was continuously extended by Ackermann, Miura and Satoh.⁴⁷ Selected examples from Miura and Ackermann are represented in Scheme 1.22, including the use of the air-stable catalyst [RuCl2(p-cymene)]2, copper(II) acetate as the oxidant and an additive.

Scheme 1.22: Ruthenium(II)-catalyzed oxidative alkenylation of benzamides.

Further improvements in the ruthenium(II)-catalyzed reactions were achieved because of the combination of reduced amounts of copper acetate monohydrate and an aerobic atmosphere (Scheme 1.23 a).⁴⁸ Particularly notable, is the functionalization of benzaldehydes (Scheme 1.23 b).

47 (a) Y. Hashimoto, T. Ortloff, K. Hirano, T. Satoh, C. Bolm, M. Miura, Chem. Lett. 2012, 41, 151–153; (b) L.

Ackermann, L. Wang, R. Wolfram, A. V. Lygin, Org. Lett. 2012, 14, 728–731; L. Ackermann, J. Pospech, Org.

Lett. 2011, 13, 4153-4155.

48 (a) K. Graczyk, W. Ma, L. Ackermann, Org. Lett. 2012, 14, 4110–4113; (b) K. Padala, S. Pimparkar, P.

Madasamy, M. Jeganmohan, Chem. Commun. 2012, 48, 7140–7142; (c) K. Padala, M. Jeganmohan, Org. Lett.

2011, 13, 6144–6147; (d) K. Padala, M. Jeganmohan, Org. Lett. 2012, 14, 1134–1137.

(26)

Scheme 1.23: Ruthenium(II)-catalyzed oxidative alkenylation of arenes under air.

Meanwhile, the standard reaction conditions using copper acetate as the oxidant is indeed convenient, however, heavy metal waste is still produced as by-product.

An elegant way of ruthenium-catalyzed reactions avoiding this waste is the use of prefunctionalized starting materials, bearing a directing group containing an internal oxidant (Scheme 1.24).⁴⁹

Scheme 1.24: Ruthenium-catalyzed oxidative alkenylation with internal oxidants.

The most abundant and inexpensive oxidant that can be used in oxidative C−H bond functionalization is air. So far, there are only few examples of C−H bond functionalization using air as the sole oxidant (Scheme 1.25). The palladium-catalyzed synthesis of chromene

49 (a) F. Yang, L. Ackermann. J. Org. Chem. 2014, 79, 12070−12082; (b) L. Ackermann, S. Fenner, Org. Lett.

2011, 13, 6548−6551.

(27)

structures by 6-endo cyclization of ortho-allylic phenols with excellent yields was reported by Larock in 1998.⁵⁰ Ideally, the reaction was accomplished with air as the oxidant.

Unfortunately, full conversion of this reaction was obtained only after three days.

Scheme 1.25: 6-endo Cyclization of ortho-allylic phenols with air as sole oxidant.

Recently, the first rhodium-catalyzed example using air as sole oxidant was published by Yu in 2015 (Scheme 1.26).⁵¹ There, N-perfluoroaryl benzamides 68c led to the ortho- alkenylation. The γ–lactam products are readily converted to the olefinated products, by treating the lactam with LiHMDS, Boc2O and sodium ethanolate.

Scheme 1.26: Rhodium-catalyzed direct alkenylation with air as terminal oxidant.

Despite this progress, applying these economic conditions remained an extremely challenging task. In contrary, the use of ambient oxygen in transition metal-catalyzed C−H bond functionalization gained more attention in recent years. In 1999, Uemura published the palladium-catalyzed oxidative ring cleavage of tert-cyclobutanols under an oxygen

50 (a) R. C. Larock, T. R. Hightower, L. A. Haswold, K. P- Peterson, J. Org. Chem. 1996, 61, 3584−3585; (b) R. C.

Larock, L. Wei, T. R. Hightower, Synlett, 1998, 5, 522−524.

51 Y. Lu, H.-W. Wang, J. E. Spangler, K. Chen, P.-P. Cui, Y. Zhao, W.-Y. Sun, J.-Q. Yu, Chem. Sci. 2015, 6, 1923−1927.

(28)

atmosphere.⁵² Based on this publication Stoltz developed the first palladium-catalyzed cyclization of heteroatoms onto pedant olefins in 2005 (Scheme 1.27).⁵³

Scheme 1.27: Palladium-catalyzed cyclization with O2 as the oxidant.

In 2009, Jiao succeeded in the synthesis of indoles from simple anilines and alkynes (Scheme 1.28).⁵⁴ The palladium catalyst used ambient oxyen and was limited to alkynes with electron withdrawing substituents.

Scheme 1.28: Palladium-catalyzed oxidative alkyne annulation with oxygen.

Subsequently, several groups reported on the palladium-catalyzed oxidative C−H bond functionalization with oxygen.⁵⁵

In spite of this progress in palladium-catalyzed oxidative reactions with oxygen as the terminal oxidant, the use of other metals remained difficult. The first rhodium-catalyzed reaction using molecular oxygen was reported by Huang in 2013, exploring a rhodium catalyst in the oxidative alkyne annulation of phenylpyridines (Scheme 1.29).⁵⁶ In 2014, Huang could expand this system for the synthesis of alkenylated indole derivatives.⁵⁷

52 T. Nishimura, K. Ohe, S. Uemura, J. Am. Chem. Soc. 1999, 121, 2645−2646.

53 R. M. Trend, Y. K. Ramtohul, B. M. Stoltz, J. Am. Soc. 2005, 127, 17778−17788.

54 Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao, Angew. Chem. Int. Ed. 2009, 48, 4572−4576.

55 (a) Y. Dong, S. Mao, Y.-R. Gao, D.-D. Guo, S.-H. Guo, B. Li, Y.-Q. Wang, RSC Adv. 2015, 5, 23727–23736; (b) Z.-L. Yan, W.-L. Chen, Y.-R. Gao, S. Mao, Y.-L. Zhang, Y.-Q. Wanga, Adv. Synth. Catal. 2014, 356, 1085–

1092; (c) G. Zhang, H. Yu, G. Qin, H. Huang, Chem. Commun. 2014, 50, 4331−4334; (d) P. Gandeepan, C.-H.

Cheng, J. Am. Chem. Soc. 2012, 134, 5738−5741; (e) Y.-H. Xu, Y. K. Chok, T.-P. Loh, Chem. Sci. 2011, 2, 1822–1825.

56 G. Zhang, L. Yang, Y. Wang, Y. Xie, H. Huang, J. Am. Chem. Soc. 2013, 135, 8850−8853.

57 L. Yang, G. Zhang, H. Huang, Adv. Synth. Catal. 2014, 356, 1509–1515.

(29)

Scheme 1.29: Rhodium-catalyzed oxidative alkyne annulation with oxygen as the oxidant.

The first ruthenium-catalyzed oxidative C−H bond functionalization with molecular oxygen was published in 2015 by Rueping.⁵⁸ The group of Rueping used a combination of [RuCl2(p-cymene)]2 and an expensive iridium photoredox-catalyst with oxygen as oxidant and silver hexaflouroantimonate as additive (Scheme 1.30).

Scheme 1.30: Ruthenium-photoredox-catalyzed oxidative alkenylation of phenoxypyridines with oxygen.

Shortly after Rueping´s report, Ackermann published the ruthenium-catalyzed C−H activation/alkyne annulation with oxygen as the sole oxidant (Scheme 1.31).⁵⁹ The mild reaction conditions with sodium acetate as carboxylate ligand in methanol at 45 °C represents a special key feature in the advancement of ruthenium(II)-catalyzed aerobic functionalization and in the synthesis of heterocyclic compounds, such as isocoumarins or phthalides.

58 D. C. Fabry, M. A. Ronge, J. Zoller, M. Rueping, Angew. Chem. Int. Ed. 2015, 54, 2801–2805.

59 S. Warratz, C. Kornhaaß, A. Cajaraville, B. Niepötter, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed. 2015, 54, 5513–5517.

(30)

Scheme 1.31: Ruthenium-catalyzed oxidative annulations of carboxylic acids with oxygen as oxidant.

1.5 C−H Bond Functionalization for the Efficient Synthesis of Heterocyclic Compounds

Heterocyclic compounds are important key structural motifs in pharmaceutical and medicinal products.⁶⁰ Scheme 1.32 presents some selected substances with heterocyclic moieties. The heterocyclic core is highlighted with red colour. The core of the diazepam is a diazepinone structure.⁶¹ Valsartan, which is used for hypertension medication, is produced up to 1000 tonnes per year.⁶² The heterocycle contained in this molecule is a tetrazole. The last key structural motif in this Scheme is an imidazole containing antibiotikum.⁶³

Scheme 1.32: Examples of heterocyclic containing pharmaceuticals.

60 Selected Reviews: a) A. Lauria, R. Delisi, F. Mingoia, A. Terenzi, A. Martorana, G. Barone, A. M. Almerico, Eur.

J. Org. Chem. 2014, 16, 3289–3306; b) D. Gonzaga, G. Tadeu, D. R. da Rocha, F. de C. da Silva, V. F.

Ferreira, Med. Chem. 2013, 13, 2850–2865; c) M. Juricek, P. H. Kouwer, A. E. Rowan, Chem. Comm. 2011, 47, 8740–8749; d) S. G. Agalve, S. R. Maujan, V. S. Pore, Chem. Asian J. 2011, 6, 2696–2718; e) C. O. Kappe, E.

Van der Eycken, Chem. Soc. Rev. 2010, 39, 1280–1290; f) K. D. Hänn, D. A. Leigh, Chem. Soc. Rev. 2010, 39, 1240–1251; g) A. H. El-Sagheer, T. Brown, Chem. Soc. Rev. 2010, 39, 1388–1405; h) A. Qin, J. W. Y. Lam, B.

Z. Tang, Chem. Soc. Rev. 2010, 39, 2522–2544.

61 Martin Wehling, Klinische Pharmakologie. 1. Aufl., Georg Thieme Verlag, Stuttgart, 2005, S. 487.

62 (a) N. B. Mistry, A. S. Westheim, S. E. Kjeldsen, Expert Opin. Pharmacother. 2006, 7, 575–581; (b) S. E.

Kjeldsen, H. R. Brunner, G. T. McInnes, P. Stolt, Aging Health, 2005, 1, 27–36.

63 (a) M. Plempel, K. Bartmann, K. H. Büchel, E. Regel, Deutsche Medizinische Wochenschrift, 1969, 94, 1356–

1367; (b) K. H. Büchel, W. Draber, E. Regel, M. Plempel, Arzneimittel-Forschung / Drug Research, 1972, 22, 1260–1272.

(31)

Because of the widespread use of heterocycles, there is a continued strong desire to synthesize these molecules in an economic way. The transition metal-catalyzed synthesis of heterocycles by alkyne annulation is of major significance. Especially cobalt-catalyzed annulations play an important role in heterocyclic chemistry, for example the Pauson-Khand reaction,⁶⁴ the Bönnemann-pyridine synthesis⁶⁵ and the Vollhardt-pyridine-synthesis,⁶⁶ which is shown in Scheme 1.33, including the reaction mechanism.

Scheme 1.33: Cobalt-catalyzed Vollhardt-pyridine-synthesis.

An important example of the palladium-catalyzed cross-coupling reaction is the Larock- synthesis of indoles (Scheme 1.34).⁶⁷ In this reaction ortho-iodoanilinine reacts with an alkyne to give the indole.

64 I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, Chem. Comm. 1971, 1, 36

65 H. Bönnemann, Angew. Chem. Int. Ed. Engl. 1978, 17, 505–515.

66 (a) K. P. Vollhardt, Angew. Chem. Int. Ed. Engl. 1984, 23, 539–556; (b) B. Heller, M. Hapke, Chem. Soc. Rev.

2007, 36, 1085−1094.

67 (a) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6690–6692; (b) R. C. Larock, E. K. Yum, M. D.

Refvik, J. Org. Chem. 1998, 63, 7652–7662.

(32)

Scheme 1.34: Larock-synthesis of indole.

The access to heterocyclic core structures via transition metal-catalyzed alkyne annulation is a very important aim and was extensively investigated by Ackermann, Fagnou, Miura and others.^{68, 69} Selected examples of rhodium-catalyzed alkyne annulations are presented in Scheme 1.35.^{55, 70}

Scheme 1.35: Rhodium-catalyzed alkyne annulation.

However, the ruthenium-catalyzed alkyne annulation was also achieved with various substrates and economical catalyst. Selected examples for ruthenium-catalyzed alkyne annulations are shown in Scheme 1.36. The ruthenium-catalyzed annulation of alkynes with benzamides leading to pyridinones is shown in Scheme 1.36 a.^68b Interestingly, Ackermann

68 (a) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651–3678; (b) L. Ackermann, A. V. Lygin, N.

Hofmann, Angew. Chem. Int. Ed. 2011, 50, 6379–6382; (c) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212–

11222; (d) S. Mochida, N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Lett. 2010, 39, 744–746; (e) D. R.

Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 18326–18339; (f) N. Guimond, K.

Fagnou, J. Am. Chem. Soc. 2009, 131, 12050–12051.

69 (g) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 16474–

16475.

70 K. Ueura, T. Satoh, M. Miura, J. Org. Chem. 2007, 72, 5362–5367.

(33)

and co-workers managed to find appropriate reaction conditions for the successful alkyne annulation with naphtholes and 2-phenylpyrazoles (Scheme 1.36 b and c).⁷¹

Scheme 1.36: Ruthenium(II)-catalyzed annulation of alkynes.

The transition metal-catalyzed synthesis of heterocycles by alkyne annulation is an important research area.

A second important field is the annulation with alkenes. In contrast to the alkyne annulation, the cyclization is due to an oxa- or aza-Michael reaction.

An early example was reported by Miura on the alkene annulation of benzoic and acrylic acids with acrylates (Scheme 1.37).⁷² A stoichiometric amount of copper acetate was not necessary.

71 (a) L. Ackermann, L. Wang, A. V. Lygin, Chem. Sci. 2012, 3, 177–180; (b) V. S. Thirunavukkarasu, M. Donati, L. Ackermann, Org. Lett. 2012, 14, 3416–3419.

(34)

Scheme 1.37: Rhodium-catalyzed annulation of alkynes with benzoic acids 66.

The proposed mechanism of this transformation is shown in Scheme 1.38.⁷³ In the first step the benzoic acid coordinates to the rhodium-catalyst to give 100. Thereafter, the cyclorhodation takes place and affords the rhodacycle 101. Subsequent alkene insertion occurs to produce the corresponding seven-membered rhodacycle 102, which undergoes β- hydride elimination. Afterwards, the nucleophilic cyclization results in 67. Reoxidation in the presence of copper(II) acetate regenerates the catalytic species.

Scheme 1.38: Mechanism of rhodium-catalyzed synthesis of phthalides 67.

72 K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407−1409.

73 S. Mochida, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2009, 74, 6295−6298.

(35)

In 2013, Lee published the rhodium-catalyzed synthesis of benzoxaphosphol oxides.⁷⁴ Subsequently, various other rhodium-catalyzed reactions were developed.^{62, 75}

Several rhodium-catalyzed alkene cyclization reactions were published in recent years (Scheme 1.39).68b, 68d-f, 73, 76 In Scheme 1.39 the versatility of this reaction is presented.

Scheme 1.39: Rhodium-catalyzed C−H olefination followed by oxa- and aza-Michael-reactions.

In 2011, Ackermann and co-workers succeeded in the first ruthenium-catalyzed C−H olefination followed by oxa-Michael reaction using benzoic acids for the synthesis of

74 T. Ryu, J. Kim, Y. Park, S. Kim, P. H. Lee, Org. Lett. 2013, 15, 3986–3989.

75 Selected examples: (a) X. Wang, H. Tang, H. Feng, Y. Li, Y. Yang, B. Zhou, J. Org. Chem. 2015, 80, 6238−6249; (b) S. Han, Y. Shin, S. Sharma, N. K. Mishra, J. Park, M. Kim, M. Kim, J. Jang, I. S. Kim, Org. Lett.

2014, 16, 2494−2497; (c) N. K. Mishra, J. Park, S. Sharma, S. Han, M. Kim, Y. Shin, J. Jang, J. H. Kwak, Y. H.

Jung, I. S. Kim, Chem. Commun. 2014, 50, 2350−2352; (d) A. M. Martínez, N. Rodríguez, R. G. Arrayás, J. C.

Carretero, Chem. Commun. 2014, 50, 6105−6107; (d) W. Xie, J. Yang, B. Wang, B. Li, J. Org. Chem. 2014, 79, 8278−8287.

76 (a) T. Ryu, J. Kim, Y. Park, S. Kim, P. H. Lee, Org. Lett. 2013, 15, 3986–3989

(36)

phthalides.⁷⁷ Further studies by Ackermann resulted in sultams.⁷⁸ Studies by Xuang resulted in the synthesis of quinazolinones (Scheme 1.40).⁷⁹

Scheme 1.40: Ruthenium-catalyzed C−H olefination followed by oxa- and aza-Michael-reactions.

1.6 Triazole Syntheses and Functionalizations

Triazoles are of great importance because of their biological and pharmaceutical properties.

The core structure of 1,2,3-triazoles can be synthesized by two main ways. In general, 1,2,3- triazoles are synthesized by the thermal 1,3-dipolar cycloadditions of alkynes and azides leading to 1,4-disubstituted 1,2,3-triazoles. This reaction was pioneered by Rolf Huisgen in 1963.⁸⁰ A major problem of this reaction was the separation of the different regioisomeric products. This problem was solved by Meldal, using copper(I) catalysts.⁸¹ A robust and useful reaction procedure was developed by Sharpless and Fokin (Scheme 1.41).⁸²

77 L. Ackermann, J. Pospech, Org. Lett. 2011, 13, 4153–4155.

78 W. Ma, R. Mei, G. Tenti, L. Ackermann, Chem. Eur. J. 2014, 20, 15248−15251.

79 Y. Zheng, W.-B. Song, S.-W. Zhang, L.-J. Xuan, Org. Biomol. Chem. 2015, 13, 6474–6478.

80 R. Huisgen, Angew. Chem. Int. Ed. Engl. 1963, 2, 565−598.

81 C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057−3064.

82 V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596−2599.

(37)

Scheme 1.41: Copper-catalyzed [3+2]-cycloaddition for the synthesis of 1,2,3-triazoles.

The complementary selectivity can be achieved by using ruthenium instead of copper catalysts, giving 1,5-disubstituted triazoles (Scheme 1.42).

Scheme 1.42: Ruthenium-catalyzed [3+2]-cycloaddition for the synthesis of 1,2,3-triazoles.

While 1,4-disubstituted triazoles can be obtained by using catalytic amounts of copper(II) acetate, the use of stoichiometric amounts of copper salts led to fully substituted 1,2,3- triazoles (Scheme 1.43).⁸³

Scheme 1.43: Copper-catalyzed synthesis of fully substituted 1,2,3-triazoles.

Fully substituted 1,2,3-triazoles can also be prepared by functionalization of the 1,4- disubstituted triazoles, with bromoalkanes and palladium complexes as catalyst (Scheme

83 Y.-M. Wu, J. Deng, Y. Li and Q.-Y. Chen, Synthesis 2005, 1314−1318.

(38)

1.44).⁸⁴ Several arylation reactions were studied with different arylating reagents, such as chlorides or tosylates.⁸⁵

Scheme 1.44: Palladium-catalyzed arylation of 1,4 disubstituted 1,2,3-triazoles.

Functionalization of 1,4-substituted triazoles through twofold C−H activation could be obtained in an intramolecular fashion (Scheme 1.45).⁸⁶

Scheme 1.45: Palladium-catalyzed intramolecular arylation of 1,4-disubstituted 1,2,3-triazoles.

Also the use of the triazole moiety as a directing group led to several functionalized substrates. One representative example is shown in Scheme 1.46.^{85, 87}

Scheme 1.46: Triazole assisted arylation.

84 (a) J. Deng, Y.-M. Wu and Q.-Y. Chen, Synthesis 2005, 2730−2738; (b) S. Chuprakov, N. Chernyak, A. S.

Dudnik, V. Gevorgyan, Org. Lett. 2007, 9, 2333−2336.

85 (a) L. Ackermann, R. Vicente and R. Born, Adv. Synth. Catal. 2008, 350, 741−748; (b) L. Ackermann, A.

Althammer and S. Fenner, Angew. Chem. Int. Ed. 2009, 48, 201−204.

86 L. Ackermann, R. Jeyachandran, H. K. Potukuchi, P. Novák, L. Büttner, Org. Lett. 2010, 12, 2056−2059.

87 (a) L. Ackermann, S. Barfüßer, J. Pospech, Org. Lett. 2010, 12, 724−726. (b) L. Ackermann, R. Born, R.

Vicente, ChemSusChem 2009, 546−549; (c) L. Ackermann, R. Vicente, Org. Lett. 2009, 11, 4922-4925; (d) L.

Ackermann, H. K. Potukuchi, D. Landsberg, R. Vicente, Org. Lett. 2008, 10, 3081-3084.

(39)

While the synthesis of 1-aryl-1,2,3-triazoles was largely described, the synthesis of 2-aryl- 1,2,3-triazoles was studied less. Still some ways to synthesize these substrates were developed.

The first regioselective approach was published by Buchwald in 2011.⁸⁸ 2H-1,2,3-triazoles were arylated with either aryl bromides or chlorides with a palladium catalyst (Scheme 1.47).

Scheme 1.47: Palladium-catalyzed arylation of 2H-1,2,3-triazoles.

Mongin and co-workers reported the copper-catalyzed cyclization of glyoxal with (aryl)hydrazones (Scheme 1.48).⁸⁹

Scheme 1.48: Copper-catalyzed synthesis of 2-aryl 1,2,3-triazoles.

Since the established synthesis of the core structures of 2H-1,2,3-triazoles, versatile functionalizations of these molecules were done. This includes the palladium-catalyzed halogenation, arylation, alkoxylation and acylation.⁹⁰ The acylation as representative C−H bond functionalization is shown in Scheme 1.49.^90d The palladium-catalyzed acylation of 2H- 1,2,3-triazoles worked with inexpensive toluene derivatives.

88 S. Ueda, M. Su, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 8944–8947.

89 F. Chevallier, T. Blin, E. Nagaradja, F. Lassagne, T. Roisnel, Y. S. Halauko, V. E. Matulis, O. A. Ivashkevichc, F. Mongin, Org. Biomol. Chem. 2012, 10, 4878–4885.

90 Q. Tian, X. Chen, W. Liu, Z. Wang, S. Shi, C. Kuang, Org. Biomol. Chem. 2013, 11, 7830–7833; (b) S. Shi, W.

Liu, P. He, C. Kuang, Org. Biomol. Chem. 2014, 12, 3576–3580; (c) S. Shi, C. Kuang, J. Org. Chem. 2014, 79, 6105−6112; (d) P. He, Q. Tian, C. Kuang, Synthesis 2015, 1309–1316.

(40)

Scheme 1.49: Palladium-catalyzed acylation of 2-aryl 1,2,3-triazoles.

The synthesis of 1,2,3-triazoles was investigated by many research groups. However, the synthesis of 1,5-disubstituted 1,2,4-triazoles was studied less. The synthesis of the core structure could be obtained by condensation of phenylhydrazine with N-formylbenzamide to give the desired triazoles (Scheme 1.50).⁹¹

Scheme 1.50: Condensation reaction to yield 1,5-disubstituted 1,2,4-triazoles.

An early transition metal-catalyzed synthesis of 1,2,4-triazoles was performed by Nagasawa in 2009.⁹² Amidines were copper-catalyzed coupled with nitriles. Another access, directly using nitriles, was developed by Ren.⁹³ The copper-catalyzed synthesis of 1,2,4-triazoles by a one-pot reaction directly using nitriles is presented in Scheme 1.51.

Scheme 1.51: Copper-catalyzed synthesis of 1,5-disubstituted 1,2,4-triazoles.

91 Q. Thompson, J. Am. Chem. Soc. 1951, 73, 5914–5915.

92 S. Ueda, H. Nagasawa, J. Am. Chem. Soc. 2009, 131, 15080–15081.

93 H. Xu, S. Ma, Y. Xu, L. Bian, T. Ding, X. Fang, W. Zhang, Y. Ren, J. Org. Chem. 2015, 80, 1789−1794.

(41)

2 Objectives

Transition metal-catalyzed C−H bond functionalization emerged as an important topic of research in organic synthesis. These C−H bond functionalizations are step-economical methods for the preparation of chemo- and site-selectively arylated, alkenylated and alkylated products. They avoid the use of prefunctionalized starting materials as are needed, for example, in cross-coupling reactions. The key task of this thesis was the ruthenium(II)- catalyzed synthesis and functionalization of heterocyclic compounds. Thus recently, Prof.

Ackermann and co-workers developed the direct alkylation reaction of aryl-pyridines, -pyrazoles and -ketimines with primary and secondary alkyl halides (Scheme 2.1).^{27, 42, 94}

Scheme 2.1: Ruthenium(II)-catalyzed alkylation of arylpyridines, -pyrazoles and -ketimines.

Herein we want to present the challenging alkylation of compounds bearing a triazole moiety, which is found in a variety of important pharmaceuticals and other valuable chemicals (Scheme 2.2).

Scheme 2.2: Ruthenium(II)-catalyzed alkylation of triazoles 123.

Further efforts focused on the extension of the ruthenium(II)-catalyzed alkenylation reactions of the aryl triazole (Scheme 2.3).

94 L. Ackermann, N. Hofmann, R. Vicente, Org. Lett. 2011, 13, 1875−1877.